Compounds which have the property of inhibiting the action of metalloproteinases involved in connective tissue breakdown such as collagenase, stromelysin and gelatinase (known as "matrix metalloproteinases", and herein referred to as MMPs) are thought to be potentially useful for the treatment or prophylaxis of conditions involving such tissue breakdown, for example rheumatoid arthritis, osteoarthritis, osteopenias such as osteoporosis, periodontitis, gingivitis, corneal epidermal or gastric ulceration, and tumour metastasis, invasion and growth. MMP inhibitors are also of potential value in the treatment of neuroinflammatory disorders, including those involving myelin degradation, for example multiple sclerosis, as well as in the management of angiogenesis dependent diseases, which include arthritic conditions and solid tumour growth as well as psoriasis, proliferative retinopathies, neovascular glaucoma, ocular tumours, angiofibromas and hemangiomas. However, the relative contributions of individual MMPs in any of the above disease states is not yet fully understood.
Metalloproteinases are characterised by the presence in the structure of a zinc(II) ionic site. It is now known that there exists a range of metalloproteinase enzymes that includes fibroblast collagenase (Type 1), PMN-collagenase, 72 kDa-gelatinase, 92 kDa-gelatinase, stromelysin, stromelysin-2 and PUMP-1 (L. M. Matrisian, Trends in Genetics, 1990, 6, 121-125).
The precise role of each of the various types of MMP in mediating different clinical disease conditions is not understood at present. However, there is some evidence that for some clinical end points individual MMP types may have a greater causative role than others. For the treatment of conditions mediated mainly by one MMP type, clearly it would be desirable to use an MMP inhibitor which selectively inhibited that MMP, or at least was significantly more potent as an inhibitor of that MMP than of other MMP types.
Many known MMP inhibitors are peptide derivatives, based on naturally occurring amino acids, and are analogues of the cleavage site in the collagen molecule. A recent paper by Chapman et al (J. Med. Chem. 1993, 36, 4293-4301) reports some general structure/activity findings in a series of N-carboxyalkyl peptides. Other known MMP inhibitors are less peptidic in structure, and may more properly be viewed as pseudopeptides or peptide mimetics. Such compounds usually having a functional group capable of binding to the active site zinc (II) ion in the MMP, and known classes include those in which the zinc binding group is a hydroxamic acid, carboxylic acid, sulphydryl, and oxygenated phosphorus (eg phosphinic acid and phosphonic acid) groups.
Three known classes of pseudopeptide or peptide mimetic MMP inhibitors have a hydroxamic acid group, an N-formyl-N-hydroxyamino, and a carboxylic acid group respectively as their zinc binding groups. With a few exceptions, such known MMPs may be represented by the structural formula (IA) ##STR2## in which X is the zinc binding hydroxamic acid (--CONHOH), N-formyl-N-hydroxyamino (--N(OH)CHO), or carboxylic acid (--COOH) group and the groups R.sub.1 to R.sub.5 are variable in accordance with the specific prior art disclosures of such compounds. The following patent publications disclose hydroxamic acid-based MMP inhibitors:
______________________________________ US 4599361 (Searle) EP-A-2321081 (ICI) EP-A-0236872 (Roche) EP-A-0274453 (Bellon) WO 90/05716 (British Bio-technology) WO 90/05719 (British Bio-technology) WO 91/02716 (British Bio-technology) WO 92/09563 (Glycomed) US 5183900 (Glycomed) US 5270326 (Glycomed) WO 92/17460 (SmithKline Beecham) EP-A-0489577 (Celltech) EP-A-0489579 (Celltech) EP-A-0497192 (Roche) US 5256657 (Sterling Winthrop) WO 92/13831 (British Bio-technology) WO 92/22523 (Research Corporation Technologies) WO 93/09090 (Yamanouchi) WO 93/09097 (Sankyo) WO 93/20047 (British Bio-technology) WO 93/24449 (Celltech) WO 93/24475 (Celltech) EP-A-0574758 (Roche) ______________________________________
The following patent publications disclose N-formyl-N-hydroxyamino-based MMP inhibitors:
______________________________________ EP-A-0236872 (Roche) ______________________________________
The following patent publications disclose carboxylic acid-based MMP inhibitors:
______________________________________ EP-A-0489577 (Celltech) EP-A-0489579 (Celltech) WO 93/24449 (Celltech) WO 93/24475 (Celltech) ______________________________________
It is generally understood in the art that for metalloproteinase inhibitors of formula (IA) variation of the zinc binding group X and the substituents R.sub.1, R.sub.2, R.sub.3, R.sub.4 and R.sub.5 can have an appreciable effect on the potency of inhibition of the metalloproteinase enzymes. As mentioned, the group X is thought to interact with metalloproteinase enzymes by binding to a zinc(II) ion in the active site. Generally the hydroxamic acid group is preferred over the carboxylic acid group in terms of inhibitory activity against the various metalloproteinase enzymes. However, the carboxylic acid group in combination with other substituents can provide selective inhibition of gelatinase. The R.sub.1, R.sub.2 and R.sub.3 groups are believed to occupy respectively the P1, P1' and P2' amino acid side chain binding sites for the natural enzyme substrate. Generally a larger R.sub.1 substituent enhances activity against stromelysin, a relatively short chain (C.sub.1 -C.sub.6)alkyl group (such as sec-butyl) at R.sub.2 is preferred for activity against collagenase.
MMP inhibitors of formula (IA) which have a degree of selectivity for gelatinases (rather than for example the collagenases, stromelysins and PUMP) have been reported, Patent publications EP-A-489577, EP-A-489579, WO-A-93/24449 and WO-A-93/24475 (all by Celltech) disclose classes of compounds characterised inter alia by R.sub.2 groups which are somewhat more extended than the short chain (C.sub.1 -C.sub.6)alkyl R.sub.2 groups preferred for collagenase inhibition. A typical preferred R.sub.2 grouping of this known kind is 3-phenylpropyl. Patent publication, EP-A-575844 (Roche) discloses compounds which possess activity against both gelatinases and stromelysin. Compounds included within the general structural type disclosed in EP-A-575844, are permitted to have R.sub.2 groups up to C.sub.12 in length, but this appears to be the maximum extension contemplated or permitted by the prior art at the R.sub.2 position, whether for gelatinase selective or non-gelatinase selective compounds.